Limb amputations cause three major types of dysfunction. Two of these occur immediately, and are direct consequences of the amputation, the loss of motor function below the amputation level; and the loss of all sensory feedback arising from the missing limb below the amputation level.
The third, more indirect dysfunctional consequence of amputation is that which is known as “phantom limb” sensations. These may occur either soon after, or at various delayed times after amputation. An amputee having such sensations may still “feel” his or her amputated limb in place. Of particular concern is phantom limb pain, where the amputee feels sensations of pain seemingly arising from the original limb
The causes for the often very vivid and disturbing phantom limb sensations reported by a majority of limb amputees are not completely understood, but it is believed that several processes are responsible Subsequent to loss of normal peripheral sensory nerve input, neurons in regions of the cerebral cortex and in particular in the primary sensory cortex associated with the amputated limb can greatly increase their receptivity to synaptic inputs arising from the sensory nerves that remain in the limb stump but are now disconnected from their sensory end-organs.
Cortical neurons can also become more receptive to sensory input arising from other regions of the body, in particular from regions that normally project to areas of cortex adjacent to the cortical areas originally dedicated to the amputated limb or body parts. This cortical response process, described as “cortical plasticity” (Ramachandran, V. S., and Hirstein, W. (1998). The Perception of Phantom Limbs. The D. O. Hebb lecture. Brain 121: 1603-1630), can manifest itself as early as 2 hours after experimental digit nerve amputation in animal models (Merzenich M M, Kaas J H, Wall J T, Sur M, Nelson R J, Felleman D J. (1983) Progression of Change Following Median Nerve Section in the Cortical Representation of the Hand in Areas 3b and 1 in Adult Owl and Squirrel Monkeys. Neuroscience 10(3):639-65); (Kaas J H. (1998) Phantoms of the Brain. Nature 391(6665):331, 333) and continues to develop for many weeks and months if peripheral nerves remain transected and cannot reestablish contact with their original or other suitable target organs.
It is believed that this greatly increased responsiveness of cortical neurons to inappropriate sensory inputs is at least partly responsible for phantom limb sensations. Phantom limb sensations are thus interpreted to arise from the missing limb or digits, even though the sensations may be triggered by sensory receptors from other body regions or by random activity in the disconnected sensory endings within the amputated limb stump.
Such phantom limb sensations may or may not include pain components. When pain is present, it is sometimes of such intensity that it becomes unbearable or extremely disabling to the amputee. One possibility which may account for the occurrence of phantom limb pain is that amputation eliminates or greatly disrupts the normal flow of sensory information arising from other modalities of sensory receptors (e.g., low-threshold cutaneous or muscle receptors) carried by larger diameter, myelinated axons. These sensory axons normally-convey non-painful information of proprioceptive and cutaneous origin such as touch, pressure, temperature, muscle length, tendon force or joint position.
An important landmark in the pain scientific literature is the work by Wall and Melzack ((1965) Pain Mechanisms: A New Theory. Science 150(699):971-9), who in the 1960's proposed the “Gate Control Theory” of pain whereby activity in large diameter touch Ab nerve fibers were hypothesized to reduce the central transmission of pain activity information carried to the spinal cord by smaller Aδ and C fibers. Although this hypothesis remains controversial, it has brought a focus on the complex interactions that can exist among parallel sensory inputs of different modalities, and on the various central and peripheral factors that can contribute to the central perception of pain. It is now generally accepted that the balance of activity in large and small diameter sensory nerve fibers is important in pain transmission in the spinal cord and brain centers.
In one theory of synaptic connectivity in the central nervous system, proposed by Wall and Melzack, synaptic input from large myelinated sensory fibers normally converge on interneurons that mediate pain pathway information and tend to inhibit the transmission of pain sensations that are conducted by smaller diameter, unmyelinated sensory nerve fibers. In the absence of proprioceptive and cutaneous information that could inhibit the transmission of pain, the pain pathways are open. The sensations of pain that reach the cortex are interpreted to arise from the missing limb or digits (thus the term “phantom limb” pain), even though the sensations may be triggered by sensory receptors from other body regions, or by random activity in pain afferents in the nerve stumps in the amputated limb or digits.
With respect to the fate of nerve fibers in amputated limbs, it is known that all nerve fibers in a severed nerve may atrophy to some extent in the sense that the fiber diameters are reduced, but the nerve cells generally remain viable in the sense that they continue to conduct electrical impulses and retain their basic synaptic connectivity patterns. It is also known that sensory fibers atrophy relatively more than motor fibers (Hoffer, J. A., Stein, R. B. and Gordon, T. (1979) Differential Atrophy of Sensory and Motor Fibers Following Section of Cat Peripheral Nerves. Brain Res. 178:347-361) and, furthermore, that large-diameter sensory fibers typically atrophy more than small-diameter sensory fibers. Similarly, large-diameter motor fibers typically atrophy more than small-diameter motor fibers. For hind limb nerves of cats that were cut and ligated over a period of 300 days, Milner et al. ((1981) The Effects of Axotomy on the Condition of Action Potentials in Peripheral Sensory and Motor Nerve Fibres. J Neurol Neurosurg Psychiatry 44(6):485-96) found that large sensory fibers had a 60% decrease in conduction velocity (CV); small sensory fibers had about a 45% decrease in CV; large motor fibers had a 40% decrease in CV: and small motor fibers had about a 20% decrease in CV. Thus, in amputated nerves, “large” and “small” nerve fibers will gradually become closer in their diameters and consequently closer in their thresholds for electrical stimulation.